HIV-1 can be preserved in the long-lived resting CD4+ T cells which form a viral reservoir in infected individuals. This reservoir may persist for many years even though the patients are usually treated with highly active antiretroviral therapy (HAART), and viral population can be recovered once HAART is stopped. Thus, the selective activation of the latently HIV-infected cells resulting in the replication of proviral genome is critical to make infected cells recognized by immune system. Our long term goal is to find the method of reactivation of HIV from latency and killing of infected cells that does not kill or destroy non-infected quiescent cells and subsequently target and eradicate the persistent HIV-1 reservoirs. We have preliminary data showing that a well-characterized stress signal, such as irradiation (IR), activated inappropriate entry of the HIV infected T cells to S phase of the cell cycle and increased viral transcription and eventual apoptosis of infected cells. Importantly, the parental uninfected cells did not demonstrate this response to the same irradiation dose. Our recently published data elucidated this phenomenon and indicated (1) increase of HIV-1 transcription via epigenetic mechanisms after the IR-induced DNA damage, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter; (2) elevated level of intracellular HIV-1 RNA and increased expression of viral proteins in the IR-treated HIV-1 infected quiescent CD4+ T cells; (3) enhancement of transcription activation in latently HIV-1infected macrophages treated with PKC agonist bryostatin 1 after IR; (4) higher death of irradiated HIV-1 chronically-infected cells via increased phosphorylation of Ser46 in p53 that is responsible for apoptosis induction. Finally, (5) exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma and certain tissue viral reservoirs. We hypothesize, that the cellular stress induced by low IR doses reactivates HIV-1 transcription from latently infected cells resulting in nuclear accumulation of Tat, activation of HIV-1 genome expression and enhanced apoptosis of infected, but not uninfected, cells. Our two aims include; A) To identify the mechanism of HIV-1 reactivation in response to therapeutic X-ray doses in latently infected T cells and to assess IR effect on the Tat activated HIV-1 transcription; and B) To decipher mechanism of enhanced apoptosis of HIV-1 infected cells in response to IR doses. The expected outcomes of these proposed studies include elucidation of the mechanisms that determine HIV-1 reactivation and apoptosis in latently infected cells and tissues in response to the X ray IR. We also expect to determine optimal IR dose that does not destroy uninfected cells, but induces HIV-1 reactivation and apoptosis of latently infected cells.